The present invention relates to substituted benzylthiazolidine-2,4-dione derivatives effective for the prevention and/or therapy of metabolic diseases such as diabetes and hyperlipidemia as agonists of peroxisome proliferator-activated receptor (abbreviated as PPAR) being nuclear receptor, in particular, as agonists of human PPAR, their addition salts, process for preparing them, and medicinal compositions containing these compounds.
The peroxisome proliferator-activated receptor(PPAR) is a ligand-dependent transcription factor that belongs to nuclear receptor superfamily similarly to steroid receptor, retinoid receptor, thyroid receptor, etc., and three isoforms (xcex1 type, xcex2 (or xcex4) type and xcex3 type) with different histological distribution have been identified hitherto in human and various animal species (Proc. Natl. Acad. Sci., 1992, 89, 4653). Thereamong, the PPARxcex1 is distributed in the liver, kidney, etc. with high catabolic capacity for fatty acids and, particularly high expression is recognized in the liver, (Endo-crinology, 1995, 137, 354), positively or negatively controlling the expressions of genes related to the metabolism and the intracellular transport of fatty acids (e.g. acyl CoA synthetic enzyme, fatty acid-binding protein and lipoprotein lipase) and apolipoprotein (AI, AII, CIII) genes related to the metabolisms of cholesterol and neutral lipid. The PPARxcex2 is expressed ubiquitously in the tissues or organisms centering around nerve cells. At present, the physiological significance of PPARxcex2 is unclear. The PPARxcex3 is highly expressed in the adipocytes and contributed to the differentiation of adipocytes (J. Lipid Res., 1996, 37, 907). In this way, each isoform of PPAR play specific functions in the particular organs and tissues.
Moreover, it is reported that a knock-out mouse of PPARxcex1 exhibits hypertriglyceridemia with ageing and becomes obesity mainly by increasing the white adipocytes (J. Biol. Chem., 1998, 273, 29577), hence the relevance between activation of PPARxcex1 and decreasing action of lipids (cholesterol and triglyceride) in blood is suggested strongly.
On the other hand, fibrates and statins are widely used so far as the therapeutic drugs for hyperlipidemia. However, the fibrates have only weak decreasing action of cholesterol, while the statins have weak decreasing action of free fatty acids and triglycerides. Moreover, with respect to the fibrates, various adverse effects such as gastrointestinal injury, anthema, headache, hepatic disorder, renal disorder and biliary calculus are reported. The reason is considered to be due to that the fibrates exhibit extensive pharmacological function.
On the other hand, it is ascertained that the major intracellular target protein of Troglitazone, Pioglitazone and Rosiglitazone being a series of thiazolidine-2,4-dione derivatives that are therapeutic drugs for type II diabetes (noninsulin-dependent diabetes) and exhibit blood glucose-decreasing action, improving action on hyperinsulinemia, etc. is PPARxcex3, and these drugs increase the transactivation of PPARxcex3 (Endocrinology, 1996, 137, 4189, Cell., 1995, 83, 803, Cell., 1995, 83, 813). Hence, PPARxcex3-activator (agonist) that can augment the transactivation of PPARxcex3 is important as antidiabetic drug.
As described, when considering the roles of transcription factor called PPAR on the function on adipocytes and the controlling mechanisms of glucose metabolism and lipid metabolism, if a compound that binds directly to as a ligand of PPAR, in particular, human PPAR and can activate human PPAR could be created, it would be reasonable to expect the medicinal use as a compound that exhibits blood glucose-decreasing action and/or decreasing action of lipids (both of cholesterol and triglyceride) in blood due to very specific mechanism.
For compounds having an affinity to PPARxcex1 as ligands of PPARxcex1, HEPE (hydroxyeicosapentaenoic acid) produced via oxidation with cytochrome P-450 and eicosanoides in HETE (hydroxyeicosatetraenoic acid) groups, in particular, 8-HETE, 8-HEPE, etc. are reported in addition to LTB., being a metabolite of arachidonic acid (Proc. Natl. Acad. Sci., 1997, 94, 312). However, these endogenous unsaturated fatty acid derivatives are unstable metabolically and chemically and cannot be offered as medicinal drugs.
Moreover, with Troglitazone, the occurrence of serious adverse effect on liver is reported rarely, hence the development of a therapeutic drug for type II diabetes with effectiveness and high safety is being sought.
Now, as compounds with similar structure to the inventive substituted benzylthiazolidine-2,4-dione derivatives, thiazolidine-2,4-dione derivatives in Japanese Unexamined Patent Publication Nos. Sho 55-22636, Sho 60-51189, Sho 61-85372, Sho 61-286376, Hei 1-131169, Hei 2-83384, Hei 5-213913, Hei 8-333355, Hei 9-48771 and Hei 9-169746, European Patent Open No. 0441605, WO-92/07839, etc. are known. However, all of these compounds are thiazolidine-2,4-dione derivatives with different structure from the inventive compounds.
With regard to patents etc. reporting the agonistic effect on PPAR xcex1, WO-97/25042, WO-97/36579, etc. are reported, but all of these have different structure from the inventive compounds and the transactivation function of PPARxcex1 is also never satisfied in strength.
Both the hyperlipidemia and the diabetes are risk factors of arterosclerosis and, from a viewpoint of the prevention of arterosclerosis, in particular, coronary arterosclerosis, the development of a therapeutic drug for metabolic diseases with effectiveness and high safety is desired clinically.
As a result of diligent studies paying an attention to such specific roles on the lipid metabolism of human PPAR, differentiation of adipocytes, etc. aiming at the creation of structurally novel drug with effectiveness and high safety as a therapeutic drug for metabolic diseases, the inventors have found that novel substituted benzylthiazolidine-2,4-dione derivatives represented by the following general formula (1) have excellent transactivation function of human PPAR, and exhibit the blood glucose-decreasing action and the lipid-decreasing action, leading to the completion of the invention.
Namely, the invention relates to the substituted benzylthiazolidine-2,4-dione derivatives represented by the general formula (1) 
[wherein R1 denotes a chlorine atom, bromine atom, nitro group, trifluoromethoxy group, ethoxy group, propoxy group or isopropoxy group, and R2 denotes a hydrogen atom or chlorine atom], their medicinally acceptable salts and their hydrates.
The salts of the compounds represented by the general formula (1) in the invention are of common use and metal salts, for example, alkali metal salts (e.g. sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g. calcium salt, magnesium salt, etc.), aluminum salt, and other pharmacologically acceptable salts are mentioned.
Furthermore, for the compounds represented by the general formula (1), the existence of various tautomers is considered. These are, for example, as shown in the following formulae. 
[wherein R1 denotes a chlorine atom, bromine atom, nitro group, trifluoromethoxy group, ethoxy group, propoxy group or isopropoxy group, and R2 denotes a hydrogen atom or chlorine atom]. In the general formula (1) aforementioned, all of these isomers and their mixtures are to be included in the scope of this invention.
According to the invention, the compounds being said the general formula (1) can be prepared, for example, through the following process (Scheme 1). 
Namely, the compounds represented by the general formula (1) can be prepared by reacting (first process) publicly known (Japanese Unexamined Patent Publication No. Hei 8-333355) compound (2) and the compounds represented by the general formula (3) 
[wherein R1 denotes a chlorine atom, bromine atom, nitro group, trifluoromethoxy group, ethoxy group, propoxy group or isopropoxy group, and R2 denotes a hydrogen atom or chlorine atom].
The first process can be performed by the leaving carboxyl group as it is, or converting it to the reactive derivative.
As the xe2x80x9creactive derivative group of the carboxyl groupxe2x80x9d, acid chloride, acid bromide, acid anhydride, carbonylimidazole or the like can be mentioned. In the case of the reaction using the reactive derivative, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence or absence of, for example, alkali metal hydride such as sodium hydride, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate, or organic base such as pyridine or triethylamine as a base.
In the case of conducting the reaction by leaving the carboxylic acid as it is, the reaction can be performed in a solvent such as methylene chloride, chloroform, dioxane or N,N-dimethylformamide in the presence of condensing agent in the presence or absence of base, in the presence or absence of additive.
As the condensing agent, for example, dicyclohexyl-carbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, diethyl cyanophosphate, diphenylphosphoric azide, carbonyldiimidazole or the like can be mentioned. As the base, for example, alkali metal hydroxide such as sodium hydroxide, alkali metal carbonate such as potassium carbonate; or organic base such as pyridine or triethylamine can be mentioned. As the additive, N-hydroxybenzotriazole, N-hydroxysuccinimide, 3,4-dihydro-3-hydroxy-4-oxo-1,2,3-benzotriazine or the like can be mentioned. The reaction can be performed at a reaction temperature of xe2x88x9220xc2x0 C. to 100xc2x0 C., preferably at 0xc2x0 C. to 50xc2x0 C.
As the administering form of the novel compounds of the invention, for example, oral administration with tablet, capsule, granule, powder, inhalant, syrup or the like, or parenteral administration with injection, suppository or the like can be mentioned.